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Publication numberUS4137300 A
Publication typeGrant
Application numberUS 05/806,424
Publication dateJan 30, 1979
Filing dateJun 14, 1977
Priority dateAug 20, 1976
Also published asDE2736794A1
Publication number05806424, 806424, US 4137300 A, US 4137300A, US-A-4137300, US4137300 A, US4137300A
InventorsPravin Sheth, Lewis J. Leeson
Original AssigneeCiba-Geigy Corporation
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Sustained action dosage forms
US 4137300 A
Abstract
By incorporating solid drug substances into mixtures of higher alkanols and/or alkanoic acids melting above 25 C, forming granules thereof and covering them with a prolamine, a pharmaceutical dosage form is obtained, which slowly and evenly releases the drug within the gastrointestinal tract of a mammal.
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Claims(13)
We claim:
1. A sustained action dosage form of the type comprising at least (a) a core-mixture of a pharmacologically effective substance and at least two members selected from a higher alkanol and alkanoic acid melting above 25 C. and (b) an outer layer of a prolamine, wherein the proportions of said effective substance: said alkanol/acid: said prolamine vary from about 100:5:3 to about 100:200:80.
2. A dosage form as claimed in claim 1, wherein the pharmacologically effective substance is a solid.
3. A dosage form as claimed in claim 1, wherein the higher alkanol is a straight chain primary alkanol with 14 to 24 carbon atoms.
4. A dosage form as claimed in claim 3, wherein the higher alkanol is cetyl or stearyl alcohol, or various mixtures thereof.
5. A dosage form as claimed in claim 1, wherein the higher alkanoic acid is a straight chain fatty acid with 14 to 24 carbon atoms.
6. A dosage form as claimed in claim 5, wherein the higher alkanoic acid is myristic, palmitic or stearic acid, or various mixtures thereof.
7. A dosage form as claimed in claim 4, wherein cetostearyl alcohol is used as alkanol mixture, containing about 24 to 50% of cetyl alcohol and about 76 to 50% of stearyl alcohol.
8. A dosage form as claimed in claim 1, wherein the prolamine is a globular protein obtained from grains.
9. A dosage form as claimed in claim 8, wherein the prolamine is zein, gliadin or hordenin, or various mixtures thereof.
10. A dosage form as claimed in claim 1, wherein said proportions for tablets vary from about 100:17:4 to about 100:25:8.
11. A dosage form as claimed in claim 1, wherein said proportions for capsules vary from about 100:25:5 to about 100:35:7.
12. A process for the preparation of sustained release dosage forms, which consists in (a) mixing a pharmacologically effective substance with at least two members selected from a higher alkanol and alkanoic acid melting above 25 C, (b) heating the mixture to about 55-65 C., c) granulating the resulting solid mixture with a solution of a prolamine, (d) evaporating the solvent of said solution and (e) compressing the resulting granules into tablets, or breaking said tablets and filling the resulting granules into capsules.
13. A process for the preparation of sustained release dosage forms, which consists in (a) mixing a pharmacologically effective substance with at least two members selected from a higher alkanol and alkanoic acid melting above 25 C., (b) granulating the resulting solid mixture with a solution of a prolamine, (c) evaporating the solvent of said solution and (d) compressing the resulting granules into tablets, or breaking said tablets and filling the resulting granules into capsules.
Description

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation-in-part of application Ser. No. 716,314, filed Aug. 20, 1976 (now abandoned).

BACKGROUND OF THE INVENTION

It is known that higher alkanols and/or alkanoic acids are useful ingredients of pharmaceutical dosage forms, either in regular tablets or in the core material of sustained release coated products. Prolamines are also known as edible coatings of food stuffs and pharmaceutical preparations, either in tablets, or smaller particles. Said materials are often utilized with other ingredients to make up highly complex mixtures, but have never been reported in the combination described below. Surprisingly it was found that the combination of said 3 or 4 basic ingredients alone results in well reproducible, sustained action dosage forms, the drug-release of which can be easily controlled by varying the relative proportions of said constituents, so that release times from about 8 to 24 hours can be achieved.

SUMMARY OF THE INVENTION

The present invention concerns and has for its object the provision of (1) a new sustained action dosage form comprising: (a) a core-mixture of a pharmacologically effective substance and at least two members selected from a higher alkanol and alkanoic acid melting above 25 C. and (b) an outer layer of a prolamine, as well as (2) a new process for the preparation of sustained release dosage forms, which consists in (c) mixing a pharmacologically effective substance with at least two members selected from a higher alkanol and alkanoic acid melting above 25 C.; if desired, heating the mixture to about 55-65 C., (d) granulating the resulting solid mixture with a solution of a prolamine, (e) evaporating the solvent of said solution and, (f) filling the resulting granules into capsules, or compressing them into tablets, if desired, with the use of other components, such as diluents, lubricants and/or disintegrating agents.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The pharmacologically effective substance is preferably a solid, also melting above 25 C., and may be either an acid or a base, but preferably a neutral substance, such as a salt.

A higher alkanol is preferably a straight chain primary alkanol with 14 to 24 carbon atoms, advantageously cetyl and stearyl alcohol, or various mixtures thereof, especially cetostearyl alcohol, which is an intimate mixture of at least 24% of cetyl alcohol and at most 76% of stearyl alcohol, but also such up to about 50% of cetyl and stearyl alcohol each. A higher alkanoic acid is also preferably a straight chain fatty acid with 14 to 24 carbon atoms, such as myristic, palmitic and/or stearic acid. A mixtures of said alcohols and acids may be used, or natural mixtures obtained from corresponding fats or waxes.

The prolamines are simple, globular proteins, preferably those obtained from grains, advantageously zein, but also gliadin and/or hordenin.

The proportions of drug substance:alcohol/acid:prolamine may vary from about 100:5:3 to about 100:200:80, for tablets preferable from about 100:17:4 to about 100:26:8, especially 100:22:6, and for capsules preferably from about 100:25:5 to about 100:35:7, especially 100:30:6. This mixture may contain additional components in order to become manageable for tabletting or capsule-filling. Said compounds are, for example diluents, such as sugars, e.g. lactose or sucrose; mannitol, cellulose, starches or calcium phosphates; or lubricants, such as alkaline earth metal salts of higher fatty acids, advantageously magnesium stearate, silica, talcum, polyethyleneglycol, teflon or vegetable fats; or disintegrating agents, such as sodium carboxymethyl-starch, other starches, alginic acid, its alkali metal salts or surface active agents, e.g. sodium lauryl sulfate. The amount of said additional components ranges from about 0.5 to 100%, preferably about 2 to 50% of the drug substance.

All the above-mentioned substances are utilized in the form of fine powders, passing sieves with openings of about 0.5 to 1.5 mm. The mixture according to (1a) is ground again and should pass through sieves with openings of about 1 to 2 mm.

In the process liquid under item (2) said drug substance and the higher alkanol or alkanoic acid can either be mixed in the form of said fine solid powder, or they are fused together, or one component is dissolved in the lower melting other component, e.g. at about 60 C. The resulting mixture is cooled and ground, if necessary, in order to obtain particles in the range between about 0.5 and about 3 mm each. They are granulated with said prolamine solution, the solvent of which is preferable a mixture of an aqueous lower alkanol and/or alkanone, advantageously ethanol or acetone, and a halogenated lower alkane, e.g. a lower alkylene chloride, advantageously methylene chloride, for example, in the proportions water:alkanol:alkylene chloride between about 1:9:10 to about 1:10:15. Said solution is gradually poured onto the former mixture so that its particles receive an outer layer of the dissolved prolamine.

The resulting wet granulate is dried in a suitable dryer, preferably between about 25 and 30 C., the dried granules blended with said lubricant and milled through a comminuting machine, if necessary.

The resulting granulate according to the invention can either be compressed into tablets, if necessary with an additional amount of lubricant, e.g. magnesium stearate, or the tablets are broken down by a comminuting machine or any suitable grinding equipment, fitted with a screen with openings preferably between 0.5 and 2 mm, and filled into hard gelatin capsules, or said granulate is filled into capsules, preferably hard gelatin capsules, as such, or in admixture with more lubricants and/or fillers, for example, silica, talcum, starches, sugars, cellulose or sodium carboxy-methyl-starch.

The resulting tablets may be conventionally film or sugar coated, either for stability or aesthetic purposes. The following examples illustrate the invention and are not to be construed as being limitations thereof. Temperatures are given in degrees Centigrade and all parts, wherever given, are parts by weight.

Example 1

Preparation of 2,000,000 tablets each containing 100 mg of drug substance:

______________________________________Formula:Tripelennamine hydrochloride                    200.00 kgCetostearyl alcohol      44.00 kgZein                     12.00 kgMagnesium stearate       6.00 kgAnhydrous ethanol        22.22 kgMethylene chloride       22.22 kgPurified water           2.77 kg______________________________________

Procedure:

The drug substance is passed through a screen with openings of about 0.5-1.5 mm to break up any lumps. It is then mixed with cetostearyl alcohol and heated until the powders fuse and form granules at about 55-65. The granules are cooled and passed through a comminuting machine and screened through openings of about 1-2 mm. The zein is suspended in the aqueous ethanol and the methylene chloride is added while mixing. The resulting solution is poured onto said granules, using suitable granulating equipment. The wet granulate is dried overnight at about 30, blended with about half the magnesium stearate, the whole milled through a comminuting machine and passed through a screen with about 0.5-2 mm openings. The granulate is mixed with the balance of the magnesium stearate and compressed into 131 mg tablets using 7.1 mm tooling.

Example 2

Preparation of 100,000 capsules each containing 100 mg of drug substance:

______________________________________Formula:Hydrochlorothiazide     10.00 kgCetostearyl alcohol     3.00 kgZein                    0.60 kgMagnesium stearate      0.25 kgAnhydrous ethanol       1.62 kgMethylene chloride      1.80 kgPurified water          0.18 kgSodium carboxymethyl-starch                   1.00 kgSilica                  0.05 kg______________________________________

Procedure:

The drug substance, cetostearyl alcohol and part of the magnesium stearate are mixed for 3 minutes and heated to 55-65 to form granules. They are cooled to 25-30 and granulated with the zein solution in the aqueous ethanolmethylene chloride. The granulate is dried overnight at 30, comminuted and passed through a screen with 2-3 mm openings. The resulting powder is mixed with 0.1 kg of magnesium stearate for 5 minutes and compressed into 2.65 g slugs of 7.2 mm thickness. They are broken in a comminuting machine, passed through a screen with 1 mm openings and the powder blended with the remaining magnesium stearate, sodium carboxymethyl-starch and silica for 10 minutes. 149 mg of the resulting mixture is filled in hard gelatin capsules, using a capsule filling machine.

Example 3

Preparation of 2,500,000 tablets each containing 50 mg of drug substance:

______________________________________Formula:Tripelennamine hydrochloride                   125.00 kgLactose anhydrous       67.50 kgCetostearyl alcohol     50.00 kgZein                    12.50 kgMagnesium stearate      7.50 kgAnhydrous ethanol       27.00 kgMethylene chloride      25.00 kgPurified water          3.00 kg______________________________________

Procedure:

According to Example 1, except that 105 mg tablets are compressed, using 6.3 mm tooling.

EXAMPLE 4

Preparation of 2,500,000 tablets each containing 10 mg of drug substance:

______________________________________Formula:Methylphenidate hydrochloride                   25.00 kgLactose                 205.00 kgCetostearyl alcohol     40.00 kgZein                    12.50 kgMagnesium stearate      5.00 kgAnhydrous ethanol       33.75 kgMethylene chloride      18.75 kgPurified water          3.75 kg______________________________________

Procedure:

According to Example 1, except that 115 mg tablets are compressed, using 6.3 mm tooling.

Example 5

Preparation of 2,000,000 tablets each containing 20 mg of drug substance:

______________________________________Formula:Methylphenidate hydrochloride                   40.00 kgCetostearyl alcohol     40.00 kgLactose                 184.00 kgZein                    12.00 kgMagnesium stearate      4.00 kgAnhydrous ethanol       32.40 kgMethylene chloride      18.00 kgPurified water          3.60 kg______________________________________

Procedure:

According to Example 1, except that 140 mg tablets are compressed, using 7.1 mm tooling.

Example 6

Preparation of 1,000,000 tablets each containing 160 mg of drug substance:

______________________________________Formula:Oxprenolol hydrochloride                   160.00 kgLactose anhydrous       30.00 kgCetostearyl alcohol     10.00 kgZein                    6.00 kgMagnesium stearate      4.00 kgAnhydrous ethanol       16.20 kgMethylene chloride      9.00 kgPurified water          1.80 kg______________________________________

Procedure:

According to Example 1, except that 237 mg tablets are compressed, using 8.7 mm tooling.

In said Examples 3 to 6, the drug substance is mixed first with the lactose and the resultant mixture is processed as the tripelennamine hydrochloride, shown in Example 1 herein.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US874310 *Jan 16, 1906Dec 17, 1907Eugene DonardPharmaceutical coating.
US2895880 *May 13, 1955Jul 21, 1959Smith Kline French LabSustained release pharmaceutical product
US3062720 *May 20, 1959Nov 6, 1962Philips RoxaneSustained release pharmaceutical tablet
US3079303 *Dec 11, 1958Feb 26, 1963Smith Kline French LabBasic tablet granulation and process of using same
US3108046 *Oct 17, 1962Oct 22, 1963Smith Kline French LabMethod of preparing high dosage sustained release tablet and product of this method
US3147187 *Sep 10, 1962Sep 1, 1964Don Hall LabSustained release pharmaceutical
US3184386 *Aug 29, 1962May 18, 1965Burroughs Wellcome CoProlonged action medicinal tablets
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Citing PatentFiling datePublication dateApplicantTitle
US4609542 *Jul 1, 1985Sep 2, 1986Elan Corporation, P.L.C.New pharmaceutical forms for administration of medicaments by oral route, with programmed release
US4680172 *Mar 5, 1985Jul 14, 1987Ciba-Geigy CorporationDevices and methods for treating memory impairment
US4690822 *Mar 12, 1986Sep 1, 1987Fujisawa Pharmaceutical Co., Ltd.Novel drug carrier and pharmaceutical preparation comprising the same
US4726951 *Jul 1, 1985Feb 23, 1988Elan Corporation P.L.C.New pharmaceutical forms for administration of medicaments by oral route, with programmed release
US4765985 *May 20, 1987Aug 23, 1988Ciba-Geigy CorporationDevices and methods for treating memory impairment
US5021248 *Sep 1, 1989Jun 4, 1991Enzytech, Inc.Hydrophobic protein microparticles and preparation thereof
US5112625 *Aug 9, 1990May 12, 1992Wm. Wrigley Jr. CompanyAqueous zein coated sweeteners and other ingredients for chewing gum
US5160742 *Dec 31, 1991Nov 3, 1992Abbott LaboratoriesSystem for delivering an active substance for sustained release
US5192563 *Dec 17, 1991Mar 9, 1993Wm. Wrigley, Jr. CompanyStrongly mint-flavored chewing gums with reduced bitterness and harshness
US5599556 *May 19, 1994Feb 4, 1997Abbott LaboratoriesProlamine coatings for taste masking
US5609909 *Apr 13, 1995Mar 11, 1997Abbott LaboratoriesProlamine coatings for taste masking
US5643905 *Jan 10, 1994Jul 1, 1997Therapie-System Gmbh & Co., KgPharmaceutical formulation for the treatment of nicotine dependence
US5869086 *Apr 25, 1994Feb 9, 1999Lts Lohmann Therapie-Systeme GmbhSystems for the controlled release of pilocarpine
US6114347 *Dec 6, 1994Sep 5, 2000Lts Lohmann Therapie-Systeme GmbhPharmaceutical formulation for the prophylaxis and pretreatment of a poisoning caused by organophosphorus cholinesterase inhibitors
US6335388Oct 2, 1998Jan 1, 2002Lavipharm Laboratories Inc.Prolamine-plant polar lipid composition, its method of preparation and applications thereof
US6361827Dec 25, 1998Mar 26, 2002Showa Sangyo Co., Ltd.Method of imparting water resistance to molded polysaccharide
US6548510Feb 8, 2000Apr 15, 2003Lts Lohmann Therapie Systeme AgPharmaceutical composition containing deoxypeganine for the treatment of nicotine dependence
US6613353Nov 22, 2000Sep 2, 2003Pii Drug Delivery, LlcPharmaceutical formulations
US6627631 *Feb 8, 2000Sep 30, 2003Lts Lohmann Therapie-Systeme AgPharmaceutical composition containing desoxypeganine for the treatment of alcoholism
US6635284Mar 11, 1998Oct 21, 2003Celegene CorporationDelivery of multiple doses of medications
US6919373Feb 19, 1999Jul 19, 2005Alza CorporationMethods and devices for providing prolonged drug therapy
US6930129Mar 8, 2001Aug 16, 2005Alza CorporationMethods and devices for providing prolonged drug therapy
US7115631Jul 16, 2002Oct 3, 2006Celgene CorporationMethods for treatment of cognitive and menopausal disorders with D-threo methylphenidate
US7431944Jun 10, 2003Oct 7, 2008Celgene CorporationDelivery of multiple doses of medications
US7459560Feb 23, 2006Dec 2, 2008Celgene CorporationProcesses and intermediates for resolving piperidyl acetamide stereoisomers
US8084059Sep 15, 2006Dec 27, 2011Alza CorporationAntidepressant dosage form
US8163798Aug 12, 2003Apr 24, 2012Alza CorporationMethods and devices for providing prolonged drug therapy
US8629179Oct 19, 2009Jan 14, 2014Alza CorporationMethods and devices for providing prolonged drug therapy
US9000038Mar 13, 2013Apr 7, 2015Alza CorporationMethods and devices for providing prolonged drug therapy
US9029416Aug 12, 2003May 12, 2015Alza CorporationMethods and devices for providing prolonged drug therapy
US9144549Mar 13, 2013Sep 29, 2015Alza CorporationMethods and devices for providing prolonged drug therapy
US9393192Apr 22, 2009Jul 19, 2016Alza CorporationMethods and dosage forms for controlled delivery of paliperidone and risperidone
US20020198234 *Jul 16, 2002Dec 26, 2002Woodcock Washburn LlpMethods for treatment of cognitive and menopausal disorders with D-threo methylphenidate
US20040091532 *Jun 10, 2003May 13, 2004Mehta Atul M.Delivery of multiple doses of medications
US20040204456 *Apr 8, 2004Oct 14, 2004Celgene CorporationMethods for treatment of cognitive and menopausal disorders with D-threo methylphenidate
US20050025831 *Aug 12, 2003Feb 3, 2005Alza CorporationMethods and devices for providing prolonged drug therapy
US20050025832 *Aug 12, 2003Feb 3, 2005Alza CorporationMethods and devices for providing prolonged drug therapy
US20050208132 *Feb 4, 2005Sep 22, 2005Gayatri SathyanMethods and dosage forms for reducing side effects of benzisozazole derivatives
US20050232995 *Feb 4, 2005Oct 20, 2005Yam Nyomi VMethods and dosage forms for controlled delivery of paliperidone and risperidone
US20050238709 *Aug 12, 2003Oct 27, 2005Alza CorporationMethods and devices for providing prolonged drug therapy
US20050239830 *Apr 26, 2004Oct 27, 2005Vikram KhetaniMethods of diminishing co-abuse potential
US20060030587 *Oct 6, 2005Feb 9, 2006Celgene CorporationMethod of treating attention deficit disorders with d-threo methylphenidate
US20060127421 *Dec 8, 2005Jun 15, 2006Celgene CorporationTreatment using D-threo methylphenidate
US20060142583 *Feb 23, 2006Jun 29, 2006Vikram KhetaniProcesses and intermediates for resolving piperidyl acetamide stereoisomers
US20060183774 *Apr 11, 2006Aug 17, 2006Celgene CorporationMethods for treatment of cognitive and menopausal disorders with D-threo methylphenidate
US20070009600 *Sep 15, 2006Jan 11, 2007Edgren David EAntidepressant dosage form
US20090062336 *Nov 12, 2008Mar 5, 2009Celgene CorporationMethods of Diminishing Co-Abuse Potential
US20090088455 *Dec 9, 2008Apr 2, 2009Celgene CorporationChronic, Bolus Adminstration Of D-Threo Methylphenidate
US20090202631 *Apr 22, 2009Aug 13, 2009Yam Nyomi VMethods and dosage forms for controlled delivery of paliperidone and risperidone
US20100093796 *Oct 19, 2009Apr 15, 2010Gupta Suneel KMethods and devices for providing prolonged drug therapy
US20110118310 *May 19, 2011Celgene CorporationTreatment Using D-Threo Methylphenidate
US20110201645 *Aug 18, 2011Zeitlin Andrew LMethod Of Treating Attention Deficit Disorders With D-Threo Methylphenidate
EP1541147A1 *Jun 9, 1998Jun 15, 2005Maghsoud M. DarianiImproved delivery of multiple doses of a methylphenidate drug
WO1998026766A1 *Dec 17, 1997Jun 25, 1998Fractales BiotechBiodegradable capsule with a prolamin base
WO1999003471A1 *Jun 9, 1998Jan 28, 1999Mehta, Atul, M.Improved delivery of multiple doses of medications
Classifications
U.S. Classification424/460, 424/468
International ClassificationA61K9/16, A61K9/64, A61K9/20, A61K9/50, A61K47/42, A61K9/48, A61K9/00, A61K47/30
Cooperative ClassificationA61K9/5052, A61K9/4866, A61K9/2013, A61K9/1617, A61K9/2063
European ClassificationA61K9/20H4, A61K9/20H6H, A61K9/50H6H, A61K9/48H6